Beta-adrenergic antagonists, or commonly referred to as beta-blockers, are important in the management of angina pectoris, hypertension and arrhythmia. The primary function of beta-blockers is to reduce the frequency of anginal episodes and raise the anginal threshold by attenuating the chronotropic and inotropic responses to adrenergic stimulation, thus diminishing myocardial oxygen consumption.
Atenolol and propranolol are two of the most commonly used beta-blockers. Atenolol is a cardioselective beta-blocker; whereas, propranolol is a nonselective beta-blocker. U.S. Pat. No. 3,836,671, issued to Barrett, et al. and assigned to Imperial Chemical Industries, discloses alkanolamine derivatives for producing beta-adrenergic blockade, and the method of producing therefor. The process disclosed therein used piperidine, which is a strong base, as a catalyst; it involved a relatively slow reaction rate (six hours to complete the reaction) and produced relatively large amounts of impurities.
In Japan Pat. Pub. 01-102,072 ('072 publication) filed by Nippon Kaya Ku (published Apr. 19, 1989), it is disclosed a process using quaternary ammonium salt of lower alkyl groups as a phase transfer catalyst during the oxygenated-alkylation step. The process disclosed in the '072 publication requires a step in which potassium hydroxide dissolved in methanol must be added as a base catalyst to convert halohydrin into epoxide before proceeding with the synthesis of the final product. Another disadvantages of this process is that methanol is known to react with epoxide to effect a nucleophilic displacement reaction thus resulting in undesirable impurities including ethers in the reaction products.